Multifunctional opioid receptor ligands and methods of treating pain

Abstract

Opioid receptor ligands (ORLs) that are multifunctional having agonist activity at mu opioid receptor (MOR), agonist activity at delta opioid receptor (DOR), and antagonist (or partial agonist) activity at kappa opioid receptor (KOR) are for the treatment of pain. The ORLs comprise peptide portions that are analogs derived from enkephalins, endomorphins, or [DArg2, Lys4]-dermorphine (DALDA), as well as tail portions that comprise a lipophilic molecule such as a 4-anilidopiperidine moiety.

What is claimed is: 
     
         1 . A method reducing pain without causing an opioid addiction in a subject in need thereof, the method comprising: administering a multifunctional compound, wherein said multifunctional compound is a mu opioid receptor (MOR) agonist, a delta opioid receptor (DOR) agonist, and a kappa opioid receptor (KOR) antagonist or partial agonist. 
     
     
         2 . The method of  claim 1 , wherein the multifunctional compound is selected from a group consisting of: SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44. 
     
     
         3 . The method of  claim 1 , wherein the multifunction compound is SEQ ID NO: 18. 
     
     
         4 . The method of  claim 1 , wherein the multifunctional compound is neuroprotective. 
     
     
         5 . The method of  claim 1 , wherein the pain is chronic pain or migraine. 
     
     
         6 . A method of modulating different opioid receptors, the method comprising blocking or limiting kappa opioid receptors (KOR) and activating mu opioid receptors (MOR) and delta opioid receptors (DOR) by using a multifunctional compound on said receptors, wherein said multifunctional compound is a MOR agonist, a DOR agonist, and KOR antagonist or partial agonist; wherein the multifunctional compound reduces opioid side effects. 
     
     
         7 . The method of  claim 6 , wherein the multifunctional compound is selected from a group consisting of: SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44. 
     
     
         8 . The method of  claim 6 , wherein the multifunction compound is SEQ ID NO: 18 
     
     
         9 . The method of  claim 6 , wherein the multifunctional compound is neuroprotective. 
     
     
         10 . A method of blocking kappa opioid receptors (KOR) and activating mu opioid receptors (MOR) and delta opioid receptors (DOR) in a subject in need thereof, the method comprising: administering a multifunctional compound to the subject, wherein said multifunctional compound is a MOR agonist, a DOR agonist, and KOR antagonist or partial agonist; wherein the multifunctional compound reduces opioid side effects in the subject. 
     
     
         11 . The method of  claim 10 , wherein the multifunctional compound is selected from a group consisting of: SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44. 
     
     
         12 . The method of  claim 10 , wherein the multifunction compound is SEQ ID NO: 18. 
     
     
         13 . The method of  claim 10 , wherein the multifunctional compound is neuroprotective.